Atherosclerosis is usually found in most major arteries, initially it is asymptomatic and not detected by most diagnostic methods. Atheroma in arm, or more often in leg arteries, which produces decreased blood flow is called peripheral arterial occlusive disease (PAOD). Cardiovascular disease including atherosclerosis is a leading cause of death in the developed world. According to United States data for the year 2004, for about 65% of men and 47% of women, the first symptom of atherosclerotic cardiovascular disease is a heart attack or sudden cardiac death (death within one hour of onset of the symptoms). Patients having such disease usually have narrowing or closing (stenosis) in one or more arteries.
The atherogenic process involves sequestration of partially oxidized lipids in the vessel wall, leading to endothelial injury that promotes adherence of mononuclear cells and platelets and contributes to phenotypic transformation of medial smooth muscle cells (SMCs) from adult to embryonic forms. The transformed smooth muscle cells proliferate and migrate to the intima of the vessel in parallel with accumulation of lipids by monocytes, causing the formation of foam cells. Other processes of plaque formation, involve T lymphocytes, platelets, cytokine release, and growth factors, which enhance migration and proliferation of SMCs. The proliferation and migration of SMCs are central to the pathogenesis of coronary artery disease. The present disclosure relates generally to methods of arresting and killing SMCs by exposing the cells to very low concentrations of an anti-proliferative, cytotoxic agent. Methods detailing the use of low levels of cytotoxic agents such as Paclitaxel (Taxol) or medical devices that are capable of providing sustained release of one or more cytotoxic therapeutic agents over a time period and in an amount effective to inhibit SMCs proliferation and/or migration are known (e.g. U.S. Pat. No. 7,919,108).
A recent review of purinergic (ATP) drugs in development focuses on synthetic agonists and antagonists of specific P2Y receptors that play a role in atherosclerosis, vascular injury, plaque formation and thrombosis (Jacobson K A, Boeynaems J-M: P2Y nucleotide receptors: Promise of therapeutic application. Drug Discov Today. 2010 July; 15(13-14): 570-578). P2Y12 receptors control platelet aggregation and antagonists of P2Y12 receptor similar to Clopidogrel (Plavix) are tested by a variety of pharmaceutical companies as anti-thrombotic drugs. P2Y receptors are involved at various steps in the inflammatory process. ATP released from neutrophils amplifies their attraction by providing chemotactic signals and its release from apoptotic cells constitutes a “find-me signal” for monocytes/macrophages. These actions are abrogated in leukocytes from P2Y2 -/- mice. Nucleotides upregulate the expression on endothelial cells of VCAM-1, that plays a crucial role in the tissue infiltration of eosinophils and monocytes. This action is P2Y2 receptor-mediated in coronary arteries, however P2Y4 and P2Y6 receptors might also be involved in other vascular beds. The approach disclosed in the present application is different in at least two aspects from the common purine drug discovery process. Applicant is not developing a new chemical entity but rather utilizing the natural agonist, ATP, for seeking and permeating into the atherosclerotic plaque. The mechanism in large part involves interactions with purine receptors. Once inside the plaque, the beta emission from the 32P-radioactive label causes destruction of cells that participate in the build-up of the plaque.
The utilization of non-32P-labeled adenine nucleotides in tumor imaging (Elmaleh D R, Zamecnik P C, Castronovo F P, Jr, Strauss H W, Rapaport E: 99mTc-labeled nucleotides as tumor-seeking radiodiagnostic agents. Proc Natl Acad Sci USA. 1984; 81(3): 918-92 and U.S. Pat. No. 6,299,857) is a method partly established by applicant. Subsequently, the administration of non-32P-labeled, radionuclide-labeled adenine nucleotides, which are derivatives of ATP, demonstrated the utility of these agents in the noninvasive imaging of atherosclerotic lesions (Elmaleh D R, Narula J, Babich J W, Petrov A, Fischman A J, Khaw B A, Rapaport E, Zamecnik P C: Rapid noninvasive detection of experimental atherosclerotic lesions with novel 99mTc-labeled diadenosine tetraphosphates. Proc Natl Acad Sci USA. 1998; 95(2): 691-695 and Elmaleh D R, Fischman A J, Tawakol A, Zhu A, Shoup T M, Hoffman U, Brownell A-L, Zamecnik P C: Detection of inflamed atherosclerotic regions with diadenosine-5′,5′″-P1,P4-tetraphosphate (Ap4A) and positron emission tomography. Proc Nat Acad Sci USA 2006; 103(43): 15992-15996). Thus, radionuclide-labeled adenine nucleotides, accumulates with high specificity in atherosclerotic lesions and in the heart.
Adenine nucleotides and ATP in particular, in a variety of physical and chemical forms including radio-nuclides were claimed and described as anti-tumor agents suitable for arrest of tumor cells without substantially affecting normal tissue (Rapaport E., U.S. Pat. Nos. 4,880,918; 5,049,372; 7,671,038; 7,879,814). Examples of such materials are adenosine 5′-monophosphate (AMP), adenosine 5′-diphosphate (ADP) and adenosine 5′-triphosphate (ATP). In addition, pharmaceutically acceptable salts, or metal complexes, or chelates, or liposomes, or radionuclides of the above compounds were recited either in the claims or in the specification of the above mentioned patents (please note U.S. Pat. No. 7,879,814). A radionuclide labeled ATP, [32P]ATP, was shown recently to be very active as an anti-tumor cytotoxic agent in established human xenographed tumors in athymic mice (Cheng Y, Yang J, Agarwal R, Green G M, Mease R C, Pomper M G, Meltzer S J, Abraham J M.: Strong Inhibition of Xenografted Tumor Growth by Low-Level Doses of [32P]ATP. Oncotarget. 2011 June; 2(6): 461-466).
Preparations containing the above ingredients can be employed in a variety of conventional pharmaceutical preparations. These preparations can contain organic or inorganic material suitable for internal administration. The high solubility of AMP and/or ADP and/or ATP salts in isotonic aqueous solutions of sodium chloride enables administration of these agents in the form of injection or infusion of single or multiple doses. The injection or infusion can be intraperitoneal, intravenous, or intra-arterial.
The established treatment of atherosclerosis and coronary artery disease consists of treatments of a variety of its underlying causes. Once this approach fails, the more direct methods undertaken are angioplasty (PTA or percutaneous transluminal angioplasty), which can be done on solitary lesions in large arteries, such as the femoral artery. Angioplasty may not have sustained benefits. Another approach involves plaque excision, whereby the plaque is scraped off out of the inside of the vessel wall. Occasionally, bypass grafting is needed to circumvent a seriously stenosed area of the arterial vasculature. Generally, the saphenous vein is used, although artificial (Gore-Tex) material is often used for large tracts when the veins are of lesser quality. Rarely, sympathectomy is used—removing the nerves that make arteries contract, effectively leading to vasodilatation. Arterial thrombosis or embolism has a dismal prognosis, but is occasionally treated successfully with thrombolytic agents.
Many treatments of the vascular or other systems entail the introduction of a device such as a stent, a catheter, a balloon, a wire guide, a cannula or the like. These devices are used to introduce cytotoxic drugs into injured arteries at a specific location. U.S. Pat. No. 7,919,108 discloses delivery of a therapeutic agent from an implantable medical device that can be desirable for a variety of applications. Occasionally, angioplasty may be followed by an abrupt closure of the vessel or by a more gradual closure of the vessel, commonly known as restenosis. Acute closure may result from an elastic rebound of the vessel wall and/or by the deposition of blood platelets and fibrin along a damaged length of the newly opened blood vessel. In addition, restenosis may result from the natural healing reaction to the injury to the vessel wall (known as intimal hyperplasia), which can involve the migration and proliferation of medial smooth muscle cells that continues until the vessel is again occluded. To prevent such vessel occlusion, stents have been implanted within a body vessel. However, restenosis may still occur over the length of the stent and/or past the ends of the stent where the inward forces of the stenosis are unopposed. To reduce this problem, one or more therapeutic agents may be administered to the patient. For example, a therapeutic agent may be administered systemically or locally administered through a catheter positioned within the body vessel near the stent, or coated on the stent itself
[99mTc]Ap4A and similar agents were successfully utilized as radiopharmaceuticals, which were shown to have potential both as radiodiagnostic agents for the rapid detection of atherosclerotic plaques and for probing the fundamental pathophysiology of atherogenesis (Elmaleh, 1998; supra). The accumulation of [18F]AppCHFppA in macrophage-rich atherosclerotic plaques was quantified noninvasively with PET (Elmaleh 2006; supra). Hence, [18F]AppCHFppA holds promise for the noninvasive characterization of vascular inflammation.